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Production of a transgenic mouse model of familial amyloidotic polyneuropathy.

Research Project

Project/Area Number 61480439
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Human genetics
Research InstitutionKumamoto University Medical School

Principal Investigator

YAMAMURA Ken-ichi  Kumamoto University Medical School, 医学部, 教授 (90115197)

Co-Investigator(Kenkyū-buntansha) WAKASUGI Shoji  Kumamoto Universuty Medical School, 医学部, 助手 (50201140)
INOMOTO Takeaki  Kumamoto University Medical School, 医学部, 助手 (60128254)
MIYAZAKI Junichi  Kumamoto University Medical School, 医学部, 助教授 (10200156)
前田 秀一郎  熊本大学, 医学部, 助教授 (10117244)
Project Period (FY) 1986 – 1987
Project Status Completed (Fiscal Year 1987)
Budget Amount *help
¥7,100,000 (Direct Cost: ¥7,100,000)
Fiscal Year 1987: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1986: ¥5,600,000 (Direct Cost: ¥5,600,000)
KeywordsFamilial amyloidotic polyneuropathy / Genetic disease / Transgenic mouse / transthyretin / プレアルブミン / マウス受精卵 / マイクロインジェクション
Research Abstract

Familial amyloidotic polyneuropathy is an autosomal dominant disorder which is characterized by extracellular deposition of amyloid fibrils and by prominent peripheral and autonomic nerve involvement. This amyloid prothein is mainyl composed of transthyretin (TTR) with a substitution of methionine for valine at position 30 in the FAP type. I. This amino acid substitution is thought to lead to amyloid deposition.
In order ot analyze the pathological process of amyloid deposition and the factor(s) other than mutant TTR gene, we have produced transgenic mice by microinjecting the cloned human mutant TTR gene into fertilized eggs of C57BL/6 mice. In order to produce large quantities of variant TTR in transgenic mice, we prepared two constructs. One is the 7.6-kilobase (kb) fragment (0.6-hTTR30) containing about 600-base pair (bp) upstream region and entire human mutant TTR gene. The other is the 7.8 kb fragment in which the promotor region was replaced with that of the mouse metallotheionein-I gene (MT-hTTR30). We produced 9 and 5 transgenic mice, respectively. There was no significant difference in serum concentrations of human mutant TTR between two lines and they ranged from 0.2 tof 5.0/mg/dl. However, the actual amount of homo-tetramers composed of human TTR (hTTR4) was 300 times higher in MT-hTTR30 than in 0.6-hTTR30 as judged from the fissue specificityf of each gene. Amyloid deposition was observed in the submucosa of alimentary tract and renal glomeruli of MT-hTTR30 line but not of 0.6-hTTR30 line. These results suggest that the presence of hTTR4 is important for amyloid deposition. But the possibility that the Xpression of hTTR gene in the choroid plexus is important for amyloid deposition cannot be ruled out from these results. We are now atempting ot produce transgenic mice by microinjecting the human mutant TTR gene containg about 6.0 kb upstream region.

Report

(2 results)
  • 1987 Final Research Report Summary
  • 1986 Annual Research Report
  • Research Products

    (6 results)

All Other

All Publications (6 results)

  • [Publications] Ken-ichi Yamamura;Shoji Wakasugi;Shuichiro Maeda;Takeaki Inomoto;Tomohisa Iwanaga;Masahiro Uehira;Kimi Araki:Jun-ichi Miyasaki;Kazunori Shimada: Developmental Genetics. 8. 195-205 (1987)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1987 Final Research Report Summary
  • [Publications] Kazunori Shimada;Shuichiro Maeda;Shoji Wakasugi;Tatsufumi Murakami;Shukuro Araki;Ken-ichi Yamamura: Enzyme. 38. 65-71 (1987)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1987 Final Research Report Summary
  • [Publications] Shoji Wakasugi;Takeaki Inomoto;Shigehiro Yi;Makoto Naito;Masahiro Uehira;Tomohisa Iwanaga;Shuichiro Maeda;Kimi Araki;Jun-ichi Miyazaki;Kiyoshi Takahashi;Kazunori Shimada;Ken-ichi Yamamura: Proc. Japan Acad.63. 344-327 (1987)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1987 Final Research Report Summary
  • [Publications] Ken-ichi Yamamura, shouji Wakasugi, Shuichiro Maeda, Takeaki Inomoto, Tomohisa Iwanaga, Masahiro Uehira, Kimi Araki, Jun-ichi Miyazaki Shimada: "Tissue-Specific and Developmental Expression of Human Transthyretin Gene In Transgenic Mice" Developmental Genetics. 8. 195-205 (1987)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1987 Final Research Report Summary
  • [Publications] Kazunori Shimada, Shuichiro Maeda, Shoji Wakasugi, Tatsufumi Murakami, Shukuro Araki, Ken-ichi Yamamura: "Molecular Genetics of Familial Amyloidotic Polyneuropathy" Enzyme. 38. 65-71 (1987)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1987 Final Research Report Summary
  • [Publications] Shoji Wakasugi, Takeaki Inomoto, Shigehiro Yi, Makoto Naito, Masahiro Uehiar, Tomohisa Iwanaga, Shuichiro Maeda, Kimi Araki, Jun-ichi Miyazaki, Kiyoshi Takahashi, Kazunori Shimada, Kin-ichi Yamamur: "A Transgenic Mouse Model of Familial Amyloidotic Polyneuropathy" Proc. Japan Acad.63. 344-347 (1987)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1987 Final Research Report Summary

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Published: 1987-03-31   Modified: 2016-04-21  

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